This statement provides a roadmap to further advance the state of knowledge, with the ultimate goal of developing RV-targeted therapies for patients with RV failure of any etiology.

Background Right ventricular (RV) functional reserve affects functional capacity and prognosis in patients with pulmonary arterial hypertension (PAH). PAH associated with systemic sclerosis (SSc-PAH) has a substantially worse prognosis as compared to idiopathic PAH (IPAH), even though many measures of resting RV function and pulmonary vascular load are similar. We therefore tested the hypothesis that RV functional reserve is depressed in SSc-PAH patients. Methods and Results RV pressure-volume relations were prospectively measured in IPAH (n=9) and SSc-PAH (n=15) patients at rest and during incremental atrial pacing or supine bicycle ergometry. Systolic and lusitropic function increased at faster heart rates in IPAH patients, but were markedly blunted in SSc-PAH. The recirculation fraction, which indexes intracellular calcium recycling, was also depressed in SSc-PAH (0.32±0.05 versus 0.50±0.05; p=0.039). At matched exercise (25 Watts), SSc-PAH patients failed to augment contractility (end-systolic elastance) whereas IPAH did (p<0.001). RV afterload assessed by effective arterial elastance rose similarly in both groups; thus, ventricular-vascular coupling declined in SSc-PAH. Both end-systolic and end-diastolic RV volumes increased in SSc-PAH patients to offset contractile deficits, whereas chamber dilation was absent in IPAH (+37±10% versus +1±8%, p=0.004, and +19±4% versus −1±6%, p<0.001, respectively). Exercise-associated RV dilation also strongly correlated with resting ventricular-vascular coupling in a larger cohort. Conclusions RV contractile reserve is depressed in SSc-PAH versus IPAH subjects, associated with reduced calcium recycling. During exercise, this results in ventricular-pulmonary vascular uncoupling and acute RV dilation. RV dilation during exercise can predict adverse ventricular-vascular coupling in PAH patients.

Background: Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH.

Rationale: Pulmonary arterial hypertension (PAH) is a medically incurable disease resulting in death from right ventricular (RV) failure. Both pulmonary vascular and RV remodeling are linked to dynamic changes in the microvasculature. Therefore, we hypothesized that circulating angiostatic factors could be linked to outcomes and represent novel biomarkers of disease severity in PAH.Objectives: We sought to determine the relationship of a potent angiostatic factor, endostatin (ES), with disease severity and mortality in PAH. Furthermore, we assessed genetic predictors of ES expression and/or function and their association with outcomes in PAH.Methods: We measured levels of serum ES in two independent cohorts of patients with PAH. Contemporaneous clinical data included New York Heart Association functional class, 6-minutewalk distance, invasive hemodynamics, and laboratory chemistries.Measurements and Main Results: Serum ES correlated with poor functional status, decreased exercise tolerance, and invasive hemodynamics variables. Furthermore, serum ES was a strong predictor of mortality. A loss-of-function, missense variant in the gene encoding ES, Col18a1, was linked to lower circulating protein and was independently associated with reduced mortality.Conclusions: Our data link increased expression of ES to disease severity in PAH and demonstrate a significant relationship with adverse outcomes. Circulating ES levels can be genetically influenced, implicating ES as a genetically determined modifier of disease severity impacting on survival. These observations support serum ES as a potential biomarker in PAH with the capacity to predict poor outcomes. More importantly, this study implicates Col18a1/ES as a potential new therapeutic target in PAH.

Background Although the transpulmonary gradient (TPG) and pulmonary vascular resistance (PVR) are commonly used to differentiate heart failure patients with pulmonary vascular disease from those with passive pulmonary hypertension (PH), elevations in TPG and PVR may not always reflect pre-capillary PH. Recently, it has been suggested an elevated diastolic pulmonary artery pressure to pulmonary capillary wedge pressure gradient (DPG) may be better indicator of pulmonary vascular remodeling, and therefore, may be of added prognostic value in patients with PH being considered for cardiac transplantation. Methods Utilizing the United Network for Organ Sharing (UNOS) database, we retrospectively reviewed all primary adult (age >17 years) orthotropic heart transplant recipients between 1998–2011. All patients with available pre-transplant hemodynamic data and PH (mean pulmonary artery pressure ≥ 25mmHg were included (n=16,811). We assessed the prognostic value of DPG on post-transplant survival in patients with PH and an elevated TPG and PVR. Results In patients with PH and a TPG > 12mmHg (n=5,827), there was no difference in survival at up to 5 years post-transplant between high (defined as ≥3, ≥5, ≥7, or ≥10mmHg) and low DPG groups (<3, <5, <7, or <10mmHg). Similarly, there was no difference in survival between high and low DPG groups in those with a PVR > 3 wood units (n=6,270). Defining an elevated TPG as > 15mmHg (n=3,065) or an elevated PVR > 5 (n=1783) yielded similar results. Conclusions In the largest analysis to date investigating the prognostic value of DPG, an elevated DPG had no impact on post-transplant survival in patients with PH and an elevated TPG and PVR.